Background: Enterovirus 71 (EV71) infection serves as a leading cause of hand-foot-and-mouth disease, and induces neural disorders. Apelin-13, as a neuropeptide, presents potential neuroprotective activities, but its short half-life in circulation has limited its clinical use. Objective: To explore the role of nano-liposomal encapsulation-delivered apelin-13 in the development of EV71 infection-induced neurodegeneration. Method: The liposome encapsulating apelin-13 (lipoPEG-A13) was successfully constructed and characterized in the study. The neurodegeneration measurement in an intracranially EV71-infected mouse model was performed in vivo. MTT assays, lactate dehydrogenase release assays, immunohistochemistry, and immunofluorescence staining qPCR assays, and Western blot analysis were respectively performed. Results: EV71 notably replicated and promoted apoptosis in the cerebral cortex from the EV71-infected mice but exhibited comparatively low replication and slightly regulated apoptosis in the cerebellum. Remarkably, lipoPEG-A13 was able to inhibit EV71-induced neurological injury in the murine cerebral cortex in vivo. Meanwhile, LipoPEG-A13 could attenuate EV71-caused apoptosis of the neural cell in the brain. LipoPEG-A13 decreased the Toll-like receptor 7 (TLR7) and interleukin-6 (IL-6) production in the mice. Apelin-13 inhibited the expression of TLR7 and IL-6 in the human astroglioma U251 cells. Apelin-13 could reduce the apoptosis of astrocytic cells infected with EV71. Conclusion: Nano-liposomal encapsulation-delivered apelin-13 attenuated EV71 infection-induced neurodegeneration via modulating IL-6 and TLR7 production. The finding provides new insights into how Nano-liposomal encapsulation-delivered apelin-13 modulates EV71 infection-induced neurological disorders. The Nano-liposomal encapsulation-delivered apelin-13 presents the application potential in the clinical context.